Benzodioxole compounds of therapeutic interest

ABSTRACT

This invention relates to benzodioxole compounds having valuable pharmacological properties and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and method of treatment therewith.

United States Patent Eriksoo et al.

BENZODIOXOLE COMPOUNDS OF THERAPEUTIC INTEREST inventors: Edgar Eriksoo;Hans Jacob Fex; Knut Berti! Hogberg; Henri Rene Mollberg, all ofHalsingborg; Oskar Adolf Rohte, Raa, all of Sweden Assignee:Aktiebolaget Leo (AB Leo), Halsovagen, Halsingborg, Sweden Filed: June24, 1969 Appl. No.: 836,142

US. Cl. ..260/340.5, 260/247.7, 260/294.7,

260/326.5, 424/278 Int. Cl. ..C07d 13/10 Field of Search ..260/340.5

[15] 3,682,973 1 Aug. 8, 1972 [56] References Cited UNITED STATESPATENTS 2,545,439 3/ 1951 Allen et al. ..260/340.5

Primary Examiner-Alex Mazel Assistant Examiner-James H. TurnipseedAttorney-Gordon W. Hueschen and Hueschen and Kurlandsky [57] ABSTRACT 45Claims, No Drawings BENZODIOXOLE COMPOUNDS F THERAPEUTIC INTEREST Thesymbols occurring below are defined when first used and have the samedefinition throughout this description.

With lower alkyl or lower alkoxy is undelstood alkyl or alkoxy groupscontaining up to four carbon atoms.

In accordance with the present invention there is provided benzodioxolecompound of the general formula:

RI%(:I

wherein R is an amino, alkylamino, dialkylamino,

morpholino, piperidino, pyrrolidino or dialkylamino alkylamino group ora group of the formula 0R wherein R is a hydrogen atom, a lower alkylgroup or a pharmaceutically acceptable inorganic or organic cation, Rand R are the same or different and each is a hydrogen atom or a loweralkyl group, R, R and R are the same or different and each is ahydrogen, fluorine or chlorine atom or a trifluoromethyl (CF nitro (N0or hydroxy group or a lower alkyl or lower alkoxy group, R is hydrogenor a lower alkyl group, R is an alkyl, alkenyl or cycloalkyl groupcontaining two to eight carbon atoms, optionally substituted with asubstituent selected from the group consisting of Cl, OH and loweralkoxy or an aryl group optionally substituted with not more than threeequal or different substituents selected from the group consisting of F,Cl, CF N0 OH, lower alkyl and lower alkoxy or R forms together with Rand the carbon atom in the 2-position of the benzodioxole ring acycloaliphatic ring containing up to seven carbon atoms.

The compounds of general Formula (I) which have one or more asymmetriccarbon atoms may exist in different possible stereoisomeric forms andthe present invention includes such stereoisomers and also the racematesof such compounds.

The compounds of this invention have valuable antiinflammatory,analgesic, and antipyretic properties. The present invention alsoprovides such antiinflammatory, analgesic, and antipyreticpharmaceutical compositions, containing a benzodioxole compound ofgeneral Formula (I) in admixture with a pharmacologically acceptablecarrier.

The pharmacological properties of the compounds of this invention varyaccording to the position and nature of the individual substituents andthey compare favorably with such known antiinflammatory agents as acetylsalicylic acid, phenylbutazone and indometacin.

These compounds of the general Formula (I) where R represents H and Rrepresents H or CPL, show especially high activity in pharmacologicaltests which indicate antiinllammatory activity. Such higher degree ofactivity is also shown by compounds wherein R stands for H or C H Thecompounds of the invention can be administered for disorders responsiveto treatment with antiinflammatory agents as such or admixed with apharmacologically acceptable solid or liquid carrier or diluent and theymay be made available in varying amounts in such pharmaceutical forms astablets, capsules, powders and aqueous or non-aqueous suspensions andsolutions.

The compounds of the invention are effective in pharrnaoological testsgenerally used for the detennination of antiinflammatory activity[aerosil-edema test as described by Th. Wagner-Jauregg et. al. Helv.Physiol. Acta 2l, 65 (1963), carrageenin-edema test as described by C.A. Winter et. al. Proc. Soc. Exp. Biol. Med. 111 544-47 (1962)],analgetic activity [writhing test as described by R. Koster et al. Fed.Proc. 18, 4l2 1959)]and antipyretic activity [yeast fever test in ratsas described by C. A. Winter in Non-steroidal Anti-inflammatory Drugs(S. Garattini and M. N. Dukes Eds) p. 190, Excerpta Medica FoundationI965].

The present invention also provides a process for the preparation of acompound of general Formula (1) herein, which comprises treating acarbonyl compound of the general formula:

R (II) or a reactive derivative derived therefrom with a dihydroxycompound of the general formula:

or a derivative derived therefrom, wherein R', R", R and R represent 32R OCC, R, R and R, respectively,

or groups which can be converted thereto by known methods, to obtain acompound of the general formula:

an R7 Rn (1V) whereafter, if necessary, the groups R'", R, R' and R' areconverted by conventional methods to R R'OC-C R, R and 11,

respectively, in such a manner that each group of the compound involvedis compatible with the process in question and protected if necessary,so that a compound of the general Formula (l) is obtained.

As a reactive derivative derived from compound of Formula (ll) an acetalaliphatic alcohol or a gem-dichloride or a gem-dibromide may be used.Also enol ethers with a lower aliphatic alcohol of those carbonylcompounds of the general Formula (ll) which can exist in enol-fonn maybe used as such reactive derivatives.

As a reactive derivative derived from the dihydroxy compound of Formula(Ill) cyclic sulphurous or carbonic ester may be used.

If a carbonyl compound of the general Formula (ll) itself or an acetalor an enolether derived therefrom is used in the reaction with adihydroxy compound of the general Formula (Ill) or a reactive derivativethereof the process may suitably be carried out in the presence of aconventional acetalization catalyst such as sulphuric, phosphoric,polyphosphoric, hydrochloric or trifluoroacetic acid, pyridinehydrochloride, calcium chloride or an aliphatic or aromatic sulphonicacid or phosphoric anhydride or an ion exchanger carrying sulphonic acidgroups.

The process is preferably carried out at a temperature between C. andthe boiling point of the reaction mixture in an inert solvent such as ahydrocarbon, chlorinated hydrocarbon, ether or ester. The carbonylcompound of Formula (ll) itself or the reactive derivative thereof maybe used as the solvent.

If the reactive derivative derived from the carbonyl compound of thegeneral Formula (II) is the corresponding gem-dichloride orgem-dibromide the reaction is preferably carried out in the presence ofa hydrogen ion acceptor such as a hydroxide, carbonate, or hydrogencarbonate of an alkali metal or alkaline earth metal or a tertiaryamine.

A compound of the general Fonnula (lV) may be converted into anothercompound of the same general formula. Thus the groups R" and R' may betransposed by transacetalization in a conventional way.

Also compounds of the general formula:

the carbonyl of a lower wherein R represents H or CH; when R" is CH;, orboth R" and R" represent aryl groups, can be converted to a compound ofthe general Formula (IV) by transacetalization with a carbonyl compoundof the general Formula (ll) in the presence of an acetalizationcatalyst.

The group R" mentioned may be an intermediate atom or group which byconventional methods can be converted to Such an atom or atom group maybe a hydrogen or halogen atom or an acetyl, carboxyl and derivatives,aldehyde or derivatives or a group of the formula RI R 4? whore R is anatom or group where R" is an atom or group which can be transformed intoR CO by known methods, such as a halogen atom or a hydroxy, cyanide,aldehyde or derivatives.

Compounds of the general Formula (I) which contain asymmetric carbonatoms if desired be resolved into their stereoisomers by conventionalmethods, such as fractional crystallization of the compounds of Formula(I) where R is an OH group, in the form of salts with optically activebases. Such stereoisomers may also be prepared by using optically activeintermediates in the synthesis.

The following examples illustrate the present invention.

EXAMPLE 1 To a mixture consisting of 10 mg ofmethyl-amethyl(3,4-dihydroxyphenyD-acetate, 6.6 g of 3-pentanone and 50ml of toluene are added 7.25 g of phosphorous pentaoxide in one portionwhile stirring vigorously. The reaction mixture is refluxed for I hour,and then cooled to room temperature. The solution containing the productis decanted off and passed through a short column of activated aluminaand then evaporated to dryness in vacuo i0 give a residue ofmethyl-a-methyl-( 2,2-diethyll ,3-benzodioxole)-5- acetate as an oil(b.p. l15-l35 C. at 0.7 mm). The crude ester is hydrolyzed with I00 mlof 2 molar potassium hydroxide in methanol by refluxing for 1.5 hours.

The a-methyl-( 2,2-diethyll ,3-benzodioxoleJ-5- acetic acid crystallizesas morpholine salt, m.p. 8 l .5 C.

The procedure of Example I is used for the preparation of:2,2-diethyl-l,3-benzodioxole-5-actic acid, m.p. 77-8 C.;

2-ethyl-2-methyll ,3-benzodioxole-5-acetic (ethanolamine salt m.p. 104C.

spiro /l ,3-benzodioxole-2,l '-cyclopentane/-5-acetic acid (ethanolaminesalt, m.p. [08 C.

spiro ll,3-benzodioxole-2,l cyclohexanel-S-acetic acid, m.p. 88C.;

Z-methyI-Z-tert. acid, m.p. 88C.;

2-methyl-2-phenyll ,3-benzodioxole-5-acetic (morpholine salt, m.p. I 10C.

Z-phenyl-l,3-benzodioxole-5-acetic acid, m.p. ll7

acid

butyll ,3-benzodioxole-S-acetic acid iZ-isopropyl-l,lbenzodioxole-S-acetic acid, m.p.

acid

2-butyl-2-methyl-l ,3-benzodioxole-5-acetic acid (morpholine salt, m.p.90 C.

2,2-dipropyl-1,3-benzodioxole-$-acetic acid (morpholine salt, mp. 62'(3.);

a-methyl-lZ-ethyl-Z-methyll ,3-benzodioxolel-5- acetic acid, m.p. 77.5C.;

a-methyl-l2-isopropyl-2methyll ,3-benzodioxole/- S-acetic acid(morpholine salt, m.p. l l 2-l C);

a-methyl-l2-methyl-2-propyll ,3-benzodioxole/-5- acetic acid (morpholinesalt, m.p. l04l04.5 C.);

a-methyl-l2-hexyl-2-methyl-1 ,3-benzodioxolel-5- acetic acid (morpholinesalt, m.p. 87.588 C.);

a-methyl-spiro I l ,3-benzodioxole-2,l cyclohexanel-S-acetic acid, m.p.l l3-l4.5 C;

a-methyl-( 2-methyl-2-phenyll ,3-benzodioxole acetic acid (morpholinesalt, m.p. l324 C.

2-( 4-methoxyphenyl 1 ,B-benzodioxole-S-acetic acid (morpholine salt,m.p. 83 C.);

2-( 2-methoxyphenyl)-2-methyll ,3-benzodioxole-5- acetic acid(morpholine salt, m.p. 92 C.);

2-( 4-methoxyphenyl )-2-methyll ,3-benzodioxole-5- acetic acid(morpholine salt, m.p. 107 C.);

2-[ 3 ,4-methylendioxyphenyl)-2-methyll ,3- benzodioxole5-acetic acid(morpholine salt, m.p. 108 C 2-( 4-chlorophenyl )-2-methyll,3-benzodioxole-5- acetic acid (morpholine salt, m.p. 108-l C.);

a,a-dimethyl-( 2 ,Z-diethyl-l ,3-benzodioxole )-5- acetic acid(morpholine salt, m.p. 73 C.);

Z-ethyI-Z-phenyll ,3-benzodioxole-5-aoetic (morpholine salt, m.p. 96C.);

2 ,2-diphenyll ,S-benzodioxole-S-acetic (morpholine salt, m.p. 120 C.

2-( 2-n-butyl )-2-methyll ,3-benzodioxole-5-acetic acid (morpholinesalt, m.p. 97 C.

2-( 3-n-pentyl)-2-methyI-l ,3-benzodioxole6-acetic acid (morpholine saltm.p. 103 C.);

2-cyclohexyl-2-ethyl-l ,S-benzodioxole-S-acetic acid (morpholine salt,m.p. 8990 C.);

Z-n-propyI-Z-phenyl-l ,3-benzodioxole-5-acetic acid (morpholine salt,mp. 96 C.);

2-( 3-chlorophenyl)- l ,B-benzodioxole-S-acetic acid (morpholine salt,m.p. 85 C.

2-methyl-2-( 3,4,5-trimethoxyphenyl)-l ,3- benzodioxole-S-acetic acid(morpholine salt, m.p. 84 C.

2-(4-chlorophenyl)-1,3-benzodioxole-5-acetic acid (morpholine salt, m.p.1 C.);

2-( 2-chlorophenyl l ,3-benzodioxole-5-acetic acid (morpholine salt,m.p. 104 C.);

2-( 3-methoxyphenyl)-l ,3-benzodioxole-5-acetic acid (morpholine salt,m.p. 94 C.);

2-( 2-methoxyphenyl)- l ,3-benzodioxole-5-acetic acid (morpholine salt,m.p. l 10 C.);

2-dimethyl-( 3-methoxyphenyl )-2-methyll ,3- benzodioxole-S-acetic acid(morpholine salt, m.p. 89

2-( 2 ,6-dichlorophenyl)- l ,3-benzodioxole-5-acetic acid (morpholinesalt, m.p. 100 C.);

2-( 3 ,4-dimethoxyphenyl l ,S-benzodioxole-S-acetic acid (morpholinesalt, m.p. 1 l2 2 -(4-toly)-l ,3 -benzodioxole-5 -acetic acid(Morpholine salt, m.p. l 18 C.);

2-( 3 ,4-methylendioxyphenyl l ,3benzodioxole-5- acetic acid, m.p. [08C.;

Z-cyclopropyl-Z-methyll ,3-benzodioxole-5-acetic acid (morpholine salt,m.p. 85 C.);

2,2-diethyl-6-chlorol ,3-benzodioxole-5-acetic acid, m.p. 95 C2-isopropyl-2-methyl-6-chloro-1,3-benzodioxole-S- acetic acid, m.p. 1 18C.;

a,a-dimethyl-(Z-isopropyl-2-methyl-l ,3-benzodioxole)-5-acetic acid(morpholine salt, m.p. 82 C.

acid

acid

a,a-dimethyl-( 2-methyl-2-phenyll ,3-benzodioxole )-5-acetic acid(morpholine salt, m.p. l0l-3 C.);

a,a-dimethyl-( Z-phenyll ,3-benzodioxole)-5-acetic acid (morpholinesalt, m.p. l034 C.);

2-ethyl-2-methyl-7-chlorol ,3-benzodioxole-5- acetic acid, m.p. l l7.5-l18 C.;

2-methyl-2-phenyl-7-chloro-l ,3-benzodioxole-5- acetic acid (morpholinesalt, m.p. l l8-l 19 C.

a-ethyl-( 2-butyl-2-methyll ,3-benzodioxole )-5- acetic acid, sodiumsalt;

7-fluoro-2-ethyl-2-methyll ,3-benzodioxole-5-acetic acid, sodium salt;

7-nitro-2,2-diethyl-l ,3-ben2odioxole-5-acetic acid, sodium salt;

7-trifluoromethy|-2-ethyl-2-methyl-l ,3-benzodioxole-S-acetic acid,sodium salt;

2-( 2-hydroxyethyl)-2-methyll ,3-benzodioxole-5- acetic acid, sodiumsalt;

2-( Z-methoxy-n-butyl )-2-methyll ,3benzodioxole- S-acetic acid, calciumsalt;

2-propenyl-l,Bbenzodioxole-S-acetic acid, calcium salt; and

2-( 2-chloropropyl)-2-methyll ,3-benzodioxole-5- acetic acid, calciumsalt.

EXAMPLE 2 A mixture consisting of 13.6 parts of benzodioxole-2- one(pyrocatecholcarbonate), 9.8 parts of cyclohexanone is refluxed until nomore carbon dioxide is evolved. The residue is distilled in vacuo togive spiro l,3-benzodioxole-2,l '-cyclohexane). B.p. 1 l6-l l9 C.; m.p.97 C.

To 19.4 parts of spiro (l,3-benzodioxole-2,l'- cyclohexane) are thenadded 20.4 parts of acetic anhydride. After cooling in ice-bath 28.2parts of a boron trifluoride-acetic acid complex (BF,- (CH,COOH areadded while stirring. The stirring is continued for 30 minutes in theice-bath and then for minutes at room temperature.

The reaction mixture is then poured in an excess of saturated aqueoussodium acetate solution, and then extracted with ether. The etherealextract is treated with activated carbon, dried over anhydrous sodiumsulphate and distilled in vacuo to give spiro (S-acetyI l,B-benzodioxole-ZJ '-cyclohexane). B.p. l923C.; m.p. 52 C.

(Willgerodt rearrangement) A mixture consisting of l 1.1 g of spiro(S-acetyl-l,3-benzodioxole-2,lcyclohexane), 2.6 g of amorphus sulphurand 7.3 g of morpholine is refluxed for 10 hours. The reaction mixtureis poured into 30 ml of absolute ethanol, whereafter the morpholide ofspiro (1,3-benzodioxole- 2,1'-cyclohexane)-5-thioacetic acidcrystallizes and is filtered 08'. The product so obtained is thenhydrolyzed by refluxing in 200 ml of a solution of 5 percent sodiumhydroxide in 50 percent ethanol for 10 hours. The reaction mixture isthen acidified and extracted with ether, treated with activated carbonand evaporated to dryness in vacuo. The residue is crystallized fromhexane vto yield the spiro (l,3-benzodioxole-2,l'cyclohexane)-5-aceticacid,m.p. 88 C.

EXAMPLE 3 A mixture consisting of 36.4 g of methyl-3,4-dihydroxy-phenylacetate, 29.4 g of cyclohexanone, 0.2

g of p-toluenesulphonic acid and 200 ml of xylene is refluxed with awater separator until the calculated amount of water is collected. Thereaction mixture is then extracted with an aqueous solution of sodiumhydroxide and evaporated to dryness in vacuo to yield methyl spiro(l,3-benzodioxole-2,l '-cyclohexane acetate as an oil.

EXAMPLE 4 EXAMPLE 5 Ten parts of 2-ethyl-2-methyl-l,3-benzodioxole-5-acetic acid are dissolved in 50 parts of methanol and 0.05 parts ofconcentrated sulphuric acid are added.

The reaction mixture is refluxed for 30 minutes and then cooled to roomtemperature.

The reaction mixture is then dissolved in ether, washed with aqueoussodium hydrogen carbonate solution. The ethereal solution is dried withanhydrous sodium sulphate and then evaporated to dryness. The residue isdistilled in vacuo to give methyl-(2-ethyl-2 methyl- 1,3-benzodioxole)-5-acetate, bp IO8.5 l 09 C. oil.

The same procedure may be used for the preparation of the followingcompounds:

isopropyl-( Z-ethyl-Zmethyll ,3-benzodioxole )-5- acetate, oil, bp 143C.

n-butyl-(Z-ethyl-Z-methyl- I ,3-benzodioxole )-5- acetate, oil, bp ]90-2C.

EXAMPLE 6 EXAMPLE 7 I00,000 tablets of 200 mg each:

acetic acid 20,000 g Lactose 5,850 8 Starch 2 000 g Gelatin 350 gGlycerol 150 g Distilled water q.s.

Talc L500 g Magnesium stearate l50 g 8 The 2,2-diethyl-l,3benzodioxole-5-acetic acid, lacrmxed with the talc and themagnesiumstearate, whereafter tablets are made.

' EXAMPLE 8 l00,000 tablets of I00 mg each: fi-methyH Z-ethyl-methyl-l,B-benzodioxole S-acetic acid. ethanolamine salt |0,000 g Lactose 6,4003 Starch 2,150 g Gelatin 250 g Glycerol I00 g Distilled water q.s.

Talc I000 g Magnesium stearate g The same procedure as in the Example 7is followed.

EXAMPLE 9 Aqueous solution for injection:

(1 -methyl-(2-ethyl-2-methyll ,3-

benzodioxole)$-acetic acid, ethanolamine salt 500 mg Sterilized water tomake Where the processes of the foregoing examples produce a compoundhaving a methyl or other alkyl group, it is to be understood that"compounds containing other alkyl groups of straight or branched natureand containing up to four carbon atoms inclusive, such as methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, or t.-butyl are prepared in thesame manner by substitution in the process of the appropriate differentalkyl starting material. Similarly, where a methoxy or other alkoxygroup is present, compounds having other alkoxy groups containingvarious alkyl groups having up to four carbon atoms inclusive areprepared in the same manner from the appropriate different alkoxystarting material. Similarly, other molecular changes within the scopeof the invention are readily made.

The compounds of the invention are generally characterized bythepharmacological activity hereinbefore stated, making them useful incounteracting certain physiological abnormalities in a living animalbody. Effective quantities of the pharmacologically active may beadministered to a living animal body in any one of various ways, foreximplantation,

Other modes of administration are cutaneously, subcutaneously, buccally,intramuscularly, and intraperitoneally.

As representative of living animal bodies which may be treated with thecompounds and compositions of the invention for alleviation of the sameand/or similar conditions as those described, in addition to humanbeings may be mentioned the following: domestic animals such as dogs andcats, and farm animals such as horses, cows, sheep, and goats.

Pharmaceutical formulations are usually prepared from a predeterminedquantity of one or more of the compounds of the invention, preferably insolid form. Such formulations may take the form of powders, elixirs,solutions, pills, capsules, pellets or tablets, with or without, butpreferably with, any one of a large variety of pharmaceuticallyacceptable vehicles or carriers. When in admixture with a pharmaceuticalvehicle or carrier, the active ingredient usually comprises from 0.01 to75 percent, preferably from O.l to percent, by weight of thecomposition. Carriers such as starch, sugar, talc, commonly usedsynthetic and natural gums or water, may be used in such compositions.Binders such as gelatine, and lubricants such as sodium stearate, may beused to form tablets. Disintegrating agents such as sodium bicarbonatemay also be included in tablets.

Although relatively small quantities of the active compounds of theinvention, even as low as 5.0 milligram, may be used in cases ofadministration to subjects having a relatively low body weight, unitdosages are preferably 5 milligrams or above and preferably 25, 50, or100 milligrams, or even higher, depending of course upon the subjecttreated and the particular result desired, as will be apparent to oneskilled in the art. Broader ranges are l to 3,000 milligrams per unitdose. The active compounds of the invention may be admixed foradministration with other pharmacologically active agents, such asanalgesics, tranquillizers, steroids or hormones, or with buffers orantacids, and the proportion of the active agent or agents in thecompositions may be varied widely. It is only necessary that the activeingredient of the invention should constitute an effective amount, i.e.,such that a suitable effective dosage will be obtained consistent withthe dosage fonn employed. Obviously, several unit dosage forms may beadministered at about the same time. The exact individual dosages aswell as daily dosages in a particular case will of course be determinedaccording to wellestablished medical and/or veterinary principles. As arule, however, when used therapeutically in human beings, the compoundsof the present invention may be administered in a quantity of 25 to5,000 milligrams per day and patient, divided in l to 4 doses, during aperiod of l day to l year.

We claim:

1. A compound of the formula:

3 is i taining three to eight carbon atoms, inclusive, said alkyl orcycloalkyl being optionally substituted with a substituent selected fromthe group consisting of Cl, OH, and lower alkoxy, or phenyl optionallysubstituted with not more than three substituems selected from the groupconsisting of F, Cl, CF N0 OH, lower alkyl, lower alkoxy, andmethylenedioxy.

2. A compound of claim 1 wherein R and R are H.

3. A compound of claim I wherein R is H and R" is CH,-,.

4. A compound of claim 1, wherein R is methyl.

5. A compound of claim 1, wherein R is methyl and R is phenyl optionallysubstituted with not more than three substituents selected from thegroup consisting of F, Cl, CF N0 OH, lower alkyl and lower alkoxy.

6. A compound of claim 1, wherein R and R are H and R is F, Cl, CF CH or7. A compound of claim 1 of the formula:

R is OR wherein R is hydrogen, lower-alkyl, or a pharmaceuticallyacceptable inorganic or organic cation, R and R are the same ordifferent and each is hydrogen or methyl, R is fluorine, chlorine,trifluoromethyl, methyl, or methoxy, R' is lower-alkyl or H, R is alkylor alkenyl containing two to eight carbon atoms inclusive, cycoalkylcontaining three to eight carbon atoms in the ring, or said alkyl orcycloalkyl having a substituent selected from the group consisting ofCl, OH, and lower-alkoxy.

8. A compound of claim 1 which is a-methyl-(2,2-

diethyll ,3-benzodioxole )-5-acetic acid.

9. A compound of claim 1 which is methylu -methyl- 2,2-diethyl-l,3-benzodioxole )-5-acetate.

10. A compound of claim 1 which is 2,2-diethyl-l ,3-

benzodioxole-S-acetic acid.

11. A compound of claim 1 which is 2-ethyl-2- methyl-l,3-benzodioxole-5-acetic acid.

12. A compound of claim 1 which is 2-methyl-2-tert.

butyl-l ,3-benzodioxole-5-acetic acid.

13. A compound of claim 1 which is 2-isopropyl-2- methyl- 1,3-benzodioxole-5-acetic acid.

14. A compound of claim 1 which is 2-methyl-2- propyll,3-benzodioxole-5-acetic acid.

15. A compound of claim 1 which is 2-isobutyl-2- methyl- 1,3-ben2ndioxole-5-acetic acid.

16. A compound of claim 1 which is 2-butyl-2-methyl-1,3-benzodioxole-5-acetic acid.

l7. A compound of claim 1 which is 2,2-dipropyll ,3-benzodioxole5-aceticacid.

18. A compound of claim 1 which is a-methyl-l2ethyl-2-methyl-1,3-benzodioxolel-5-acetic acid.

19. A compound of claim I which is a-methyl-l2- isopropyl-Z-methyll,J-benzodioxolel-S-acetic acid.

20. A compound of claim I which is a-methyl-IZ- methyl-Z-propyll,3-benzodioxolel-5-acetic acid.

21. A compound of claim 1 which is a-methyl-IZ- hexyl-2-methyll,3-benzodioxole/-5-acetic acid.

22. A compound of claim 1 which isa -dimethyl- 2,2-diethyll,3-benzodioxole )--acetic acid.

23. A compound of claim 1 which is 2-(2-n-butyl)-2- methyl-l,B-benzodioxole-S-acetic acid.

24. A compound of claim I which is 2-( 3-n-pentyl)2 -methyl-1,3-benzodioxole-S-acetic acid.

25. A compound of claim 1 which is 2-cyclohexyl 2- ethyll,3-benzodioxole-5 -acetic acid.

26. A compound of claim 1 which is 2-cyclopropyl-2- methyl- 1,3-benzodioxole-5 -acetic acid.

27. A compound of claim 1 which is 2,2-diethyl-6- chlorol,3-benzodioxole-5-acetic acid.

28. A compound of claim 1 which is a.a-dimethyl- (2-isopropyl-2-methyll,3-benzodioxole)-5-acetic acid.

29. A compound of claim I which is 2-ethyl-2- methyl-7-chloro-l,3-benzodioxole-5-acetic acid.

30. A compound of claim 1 which is 7-fluoro-2-ethyl- 2-methyll,3-benzodioxole'5-acctic acid.

31. A compound of claim 1 which is 7-nitro-2,2- diethyl-l,3-benzodioxole-5-acetic acid.

32. A compound of claim 1 which is 7- tIifluOrOmethyLZ-eIhyl-Z-methyll,3-benzodioxole-5- acetic acid.

33. A compound of claim 1 which is 2-(2-hydroxyethyD-Z-methyl-l,3-benzodioxole-5-acetic acid.

34. A compound of claim 1 which is 2-( Z-methoxy-n- 12 butyl )-2-me!hyl-I ,3-benzodioxole-5-acetic acid.

35. A compound of claim 1 which is 2-(2- chloropropyl )-2-met.hyll,B-benzodioxole-S-acetic acid.

36. A compound of claim 1 which is methyH 2-ethyl- Z-methyll,B-benmdioxole )-5-acetate.

37. A compound of claim 1 which is isopropyi-(Z- ethyl-Z-methyl-l,3-benzoclioxolc )-5-acetate.

38. A compound of claim 1 which is n-butyl-( Z-ethyl- Z-methyl-l,B-benzodioxole )-5-acetate.

39. A compound of claim 1 which is lower-alkyl-(Z- ethyl-Z-methyll,3-benzodioxole)-5-acetate.

40. A compound of claim 1 which is a 2-lower-alkyl- 6-chloro compound.

41. A compound of claim 1 which is a 2-lower-alkyl- 7-chloro compound.

42. A compound of claim 1 7-fluoro compound.

43. A compound of claim 1 which is 2-isopropyll ,3-benzodioxole-S-acetic acid.

44. A compound of claim 1 which is alpha-ethyl-Z- butyl-Z-methyll,-3-benzodioxole-5-acetic acid.

45. A compound of claim 1 which is 2-propenyl-l ,3-benzodioxole-S-acetic acid.

which is a 2-lower-alkyl- UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION 8 August 1972 3 682 973 Dated Patent No.

Edgar Eriksoo et a1.

Inventor(s) It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Col. 1, lines 11-17 Page 1, lines 13-17 (General Formula I) ('-'a" wasomitted) 01 line 49 "Z-dimethyl-(B- 'Eag line 12 Col. 5, line 56 "2-(4-t0ly)- Page 9,

"EB-methyl Col. 8, line 11 (Example 8) u-methyl Page 13, line 27 Signedand sealed this 20th day of March 1973.

(SEAL) Attest:

ROBERT GOT'ISCHALK EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer FORM PO-105O (IO-69]

2. A compound of claim 1 wherein R2 and R3 are H.
 3. A compound of claim1 wherein R2 is H and R3 is CH3.
 4. A compound of claim 1, wherein R7 ismethyl.
 5. A compound of claim 1, wherein R7 is methyl and R8 is phenyloptionally substituted with not more than three substituents selectedfrom the group consisting of F, Cl, CF3, NO2, OH, lower alkyl and loweralkoxy.
 6. A compound of claim 1, wherein R4 and R5 are H and R6 is F,Cl, CF3, CH3, or OCH3.
 7. A compound of claim 1 of the formula: whereinR1 is OR9 wherein R9 is hydrogen, lower-alkyl, or a pharmaceuticallyacceptable inorganic or organic cation, R2 and R3 are the same ordifferent and each is hydrogen or methyl, R6 is fluorine, chlorine,trifluoromethyl, methyl, or methoxy, R7 is lower-alkyl or H, R8 is alkylor alkenyl containing two to eight carbon atoms inclusive, cycoalkylcontaining three to eight carbon atoms in the ring, or said alkyl orcycloalkyl having a substituent selected from the group consisting ofCl, OH, and lower-alkoxy.
 8. A compound of claim 1 which is Alpha-methyl-(2,2-diethyl-1,3-benzodioxole)-5-acetic acid.
 9. A compound ofclaim 1 which is methyl- Alpha-methyl-(2,2-diethyl-1,3-benzodioxole)-5-acetate.
 10. A compound ofclaim 1 which is 2,2-diethyl-1,3-benzodioxole-5-acetic acid.
 11. Acompound of claim 1 which is 2-ethyl-2-methyl-1,3-benzodioxole-5-aceticacid.
 12. A compound of claim 1 which is 2-methyl-2-tert.butyl-1,3-benzodioxole-5-acetic acid.
 13. A compound of claim 1 which is2-isopropyl-2-methyl-1,3-benzodioxole-5-acetic acid.
 14. A compound ofclaim 1 which is 2-methyl-2-propyl-1,3-benzodioxole-5-acetic acid.
 15. Acompound of claim 1 which is2-isobutyl-2-methyl-1,3-benzodioxole-5-acetic acid.
 16. A compound ofclaim 1 which is 2-butyl-2-methyl-1,3-benzodioxole-5-acetic acid.
 17. Acompound of claim 1 which is 2,2-dipropyl-1,3-benzodioxole-5-aceticacid.
 18. A compound of claim 1 which is Alpha-methyl-/2-ethyl-2-methyl-1,3-benzodioxole/-5-acetic acid.
 19. Acompound of claim 1 which is Alpha-methyl-/2-isopropyl-2-methyl-1,3-benzodioxole/-5-acetic acid.
 20. Acompound of claim 1 which is Alpha-methyl-/2-methyl-2-propyl-1,3-benzodioxole/-5-acetic acid.
 21. Acompound of claim 1 which is Alpha-methyl-/2-hexyl-2-methyl-1,3-benzodioxole/-5-acetic acid.
 22. Acompound of claim 1 which is Alpha , Alpha -dimethyl-(2,2-diethyl-1,3-benzodIoxole)-5-acetic acid.
 23. A compound of claim 1which is 2-(2-n-butyl)-2-methyl-1,3-benzodioxole-5-acetic acid.
 24. Acompound of claim 1 which is2-(3-n-pentyl)-2-methyl-1,3-benzodioxole-5-acetic acid.
 25. A compoundof claim 1 which is 2-cyclohexyl-2-ethyl-1,3-benzodioxole-5-acetic acid.26. A compound of claim 1 which is2-cyclopropyl-2-methyl-1,3-benzodioxole-5-acetic acid.
 27. A compound ofclaim 1 which is 2,2-diethyl-6-chloro-1,3-benzodioxole-5-acetic acid.28. A compound of claim 1 which is Alpha , Alpha-dimethyl-(2-isopropyl-2-methyl-1,3-benzodioxole)-5-acetic acid.
 29. Acompound of claim 1 which is 2-ethyl-2-methyl-7-chloro-1,3-benzodioxole-5-acetic acid.
 30. A compound of claim 1 which is7-fluoro-2-ethyl-2-methyl-1, 3-benzodioxole-5-acetic acid.
 31. Acompound of claim 1 which is7-nitro-2,2-diethyl-1,3-benzodioxole-5-acetic acid.
 32. A compound ofclaim 1 which is7-trifluoromethyl-2-ethyl-2-methyl-1,3-benzodioxole-5-acetic acid.
 33. Acompound of claim 1 which is2-(2-hydroxyethyl)-2-methyl-1,3-benzodioxole-5-acetic acid.
 34. Acompound of claim 1 which is2-(2-methoxy-n-butyl)-2-methyl-1,3-benzodioxole-5-acetic acid.
 35. Acompound of claim 1 which is2-(2-chloropropyl)-2-methyl-1,3-benzodioxole-5-acetic acid.
 36. Acompound of claim 1 which ismethyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate.
 37. A compound ofclaim 1 which isisopropyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate.
 38. A compoundof claim 1 which is n-butyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate.
 39. A compound of claim 1 which islower-alkyl-(2-ethyl-2-methyl-1,3-benzodioxole)-5-acetate.
 40. Acompound of claim 1 which is a 2-lower-alkyl-6-chloro compound.
 41. Acompound of claim 1 which is a 2-lower-alkyl-7-chloro compound.
 42. Acompound of claim 1 which is a 2-lower-alkyl-7-fluoro compound.
 43. Acompound of claim 1 which is 2-isopropyl-1,3-benzodioxole-5-acetic acid.44. A compound of claim 1 which isalpha-ethyl-2-butyl-2-methyl-1,-3-benzodioxole-5-acetic acid.
 45. Acompound of claim 1 which is 2-propenyl-1,3-benzodioxole-5-acetic acid.